Heterocyclic compounds as immunomodulators

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.16/296,563, filed on Mar. 8, 2019; which is a continuation of U.S.patent application Ser. No. 15/850,221, filed on Dec. 21, 2017; whichclaims the benefit of U.S. Provisional Application No. 62/487,341, filedon Apr. 19, 2017; and U.S. Provisional Application No. 62/438,001, filedon Dec. 22, 2016, each of which is incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds modulate PD-1/PD-L1protein/protein interaction and are useful in the treatment of variousdiseases including infectious diseases and cancer.

BACKGROUND OF THE INVENTION

The immune system plays an important role in controlling and eradicatingdiseases such as cancer. However, cancer cells often develop strategiesto evade or to suppress the immune system in order to favor theirgrowth. One such mechanism is altering the expression of co-stimulatoryand co-inhibitory molecules expressed on immune cells (Postow et al, J.Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitoryimmune checkpoint, such as PD-1, has proven to be a promising andeffective treatment modality.

Programmed cell death-1 (PD-1), also known as CD279, is a cell surfacereceptor expressed on activated T cells, natural killer T cells, Bcells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). Itfunctions as an intrinsic negative feedback system to prevent theactivation of T-cells, which in turn reduces autoimmunity and promotesself-tolerance. In addition, PD-1 is also known to play a critical rolein the suppression of antigen-specific T cell response in diseases likecancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245;Postow et al, J. Clinical Oncol 2015, 1-9).

The structure of PD-1 consists of an extracellular immunoglobulinvariable-like domain followed by a transmembrane region and anintracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). Theintracellular domain contains two phosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptortyrosine-based switch motif, which suggests that PD-1 negativelyregulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al,Nat Immunol 2001, 2, 261-268), and they differ in their expressionpatterns. PD-L1 protein is upregulated on macrophages and dendriticcells in response to lipopolysaccharide and GM-CSF treatment, and on Tcells and B cells upon T cell receptor and B cell receptor signaling.PD-L1 is also highly expressed on almost all tumor cells, and theexpression is further increased after IFN-γ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). Infact, tumor PD-L1 expression status has been shown to be prognostic inmultiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al,Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2expression, in contrast, is more restricted and is expressed mainly bydendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation ofPD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal thatinhibits IL-2 and IFN-γ production, as well as cell proliferationinduced upon T cell receptor activation (Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34). Themechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibitT cell receptor signaling such as Syk and Lck phosphorylation (Sharpe etal, Nat Immunol 2007, 8, 239-245).

Activation of the PD-1 signaling axis also attenuates PKC-θ activationloop phosphorylation, which is necessary for the activation of NF-□B andAP1 pathways, and for cytokine production such as IL-2, IFN-γ and TNF(Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate thatPD-1 and its ligands negatively regulate immune responses.PD-1-deficient mice have been shown to develop lupus-likeglomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using anLCMV model of chronic infection, it has been shown that PD-1/PD-L1interaction inhibits activation, expansion and acquisition of effectorfunctions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439,682-7). Together, these data support the development of a therapeuticapproach to block the PD-1-mediated inhibitory signaling cascade inorder to augment or “rescue” T cell response. Accordingly, there is aneed for new compounds that block PD-1/PD-L1 protein/proteininteraction.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound disclosed herein, or a pharmaceutically acceptablesalt or a stereoisomer thereof, and one or more pharmaceuticallyacceptable excipient or carrier.

The present disclosure further provides methods of inhibiting PD-1/PD-L1interaction, said method comprising administering to a patient acompound disclosed herein, or a pharmaceutically acceptable salt or astereoisomer thereof.

The present disclosure further provides methods of treating a disease ordisorder associated with inhibition of PD-1/PD-L1 interaction, saidmethod comprising administering to a patient in need thereof atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt or a stereoisomer thereof.

The present disclosure further provides a method of enhancing,stimulating and/or increasing the immune response in a patient, saidmethod comprising administering to the patient in need thereof atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt or a stereoisomer thereof.

DETAILED DESCRIPTION I. Compounds

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

-   -   ring A is 5- to 14-membered heteroaryl, 4- to 14-membered        heterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5-        to 14-membered heteroaryl and 4- to 14-membered heterocycloalkyl        each has 1-4 heteroatoms as ring members selected from N, B, P,        O and S, wherein the N or S atom as ring members is optionally        oxidized and one or more carbon atoms as ring members are each        optionally replaced by a carbonyl group; and wherein ring A is        optionally substituted with 1, 2, 3, 4 or 5 R⁶ substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, —C(═S)NR¹³—, —NR¹³C(═S)—,—C(═NR¹³)NR¹³—, —NR¹³C(═NR¹³)—, —C(═NOR¹³)NR¹³—, —NR¹³C(═NOR¹³)—,—C(═NCN)NR¹³—, —NR¹³C(═NCN)—, O, —(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)_(q)—O—,—O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—, —NR¹³—(CR¹⁴R¹⁵)_(q)—,—CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—, —NR¹³SO₂NR¹³—, —NR¹³C(O)O— or—NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),C(O)NR^(a)S(O)₂R^(a), NR^(a)C(═NR^(a))R^(a), S(O)₂NR^(a)C(O)R^(a),—P(O)RaRa, —P(O)(OR^(a))(OR^(a)), —B(OH)₂, —B(OR^(a))₂, andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 R^(b) substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),C(O)NR^(a)S(O)₂R^(a), NR^(a)C(═NR^(a))R^(a), S(O)₂NR^(a)C(O)R^(a),—P(O)R^(a)R^(a), —P(O)(OR^(a))(OR^(a)), —B(OH)₂, —B(OR^(a))₂, andS(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(e) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR_(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c),C(O)NR^(c)S(O)₂R^(c), NR^(c)C(═NR^(c))R^(c), S(O)₂NR^(c)C(O)R^(c),—P(O)R^(c)R^(c), —P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂, andS(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), C(O)NR^(c)S(O)₂R^(c),NR^(c)C(═NR^(c))R^(c), S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c),—P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂, and S(O)₂NR^(g)R^(g);wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents;

each R^(n) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o),OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), C(O)NR^(c)S(O)₂R^(c),NR^(c)C(═NR^(c))R^(c), S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c),—P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂, and S(O)₂NR^(o)R^(o),wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2 or 3 R^(p) substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r), C(O)NR^(c)S(O)₂R^(c),NR^(c)C(═NR^(c))R^(c), S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c),—P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR)₂, and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), C(O)NR^(c)S(O)₂R^(c),NR^(c)C(═NR^(c))R^(c), S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c),—P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂, and S(O)₂NR^(i)R^(i),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NH OR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), C(O)NR^(c)S(O)₂R^(c),NR^(c)C(═NR^(c))R^(o), S(O)₂NR^(c)C(O)R^(c), —P(O)R^(c)R^(c),—P(O)(OR^(c))(OR^(c)), —B(OH)₂, —B(OR^(c))₂, and S(O)₂NR^(k)R^(k),wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 4-10 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, or 1, 2, or 3 independentlyselected R^(q) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 107-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents, or 1, 2, or 3 independentlyselected R^(q) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alky)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with 1, 2 or 3substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, presented herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 14-membered heteroaryl, 4- to 14-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₄ cycloalkyl, wherein the 5- to14-membered heteroaryl and 4- to 14-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂—,—NR¹³SO₂NR¹³—, —NR¹³C(O)O— or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₄ cycloalkyl, 5-14 membered heteroaryl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₄ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-14 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 R^(b) substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄haloalkyl,C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents;

each R^(n) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o),OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2 or 3 R^(p) substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR_(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁-6 haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 4-10 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 107-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9-, 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alky)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with 1, 2 or 3substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiment, presented herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀ cycloalkyl, wherein the 5- to10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,—(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q)—, —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q)—, —CH═CH—, —C≡C—, —SO₂NR¹³—, —NR¹³SO₂, —NR¹³C(O)O—or —NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R¹⁷ are each independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ and R¹⁷ are each optionallysubstituted with 1, 2, 3, 4 or 5 R^(b) substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(e)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(b) are each further optionally substituted with 1, 2 or 3independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents;

each R^(n) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o),OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2 or 3 R^(p) substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)'S(O)₂R^(i), NR^(i)'S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁-4 haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(r) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alky)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with 1, 2 or 3substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 10-membered heteroaryl, 4- to 11-memberedheterocycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀ cycloalkyl, wherein the 5- to10-membered heteroaryl and 4- to 11-membered heterocycloalkyl each has1-4 heteroatoms as ring members selected from N, O and S, wherein the Nor S atom as ring members is optionally oxidized and one or more carbonatoms as ring members are each optionally replaced by a carbonyl group;and wherein ring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶substituents;

L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, O, —(CR¹⁴R¹⁵)_(q)—,(CR¹⁴R¹⁵)_(q)—O—, —O(CR¹⁴R¹⁵)_(q), —NR¹³—, —(CR¹⁴R¹⁵)_(q)—NR¹³—,—NR¹³—(CR¹⁴R¹⁵)_(q), —CH═CH—, —C≡C—, SO₂NR¹³—, NR¹³SO₂, —NR¹³C(O)O— or—NR¹³C(O)NR¹³—;

R³ is methyl, halo, CN or C₁₋₄ haloalkyl;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂;

R⁶ and R⁷ are each independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁶ are each optionally substituted with1, 2, 3, 4 or 5 R^(b) substituents;

or two R⁶ substituents attached to the same ring carbon atom takentogether with the ring carbon atom to which they are attached form spiroC₃₋₆ cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 independently selectedR^(f) substituents;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyland —N(C₁₋₄ alkyl)₂;

R¹⁴ and R¹⁵ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R¹⁴ or R¹⁵ are eachoptionally substituted with 1, 2, or 3 independently selected R^(q)substituents;

or R¹⁴ and R¹⁵ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or6-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-of R^(e) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c);

wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1, 2 or 3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(o) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;

each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents;

each R^(n) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(o),OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o), whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(n) are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1, 2 or 3 R^(p) substituents;

each R^(p) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r),OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally substituted with 1,2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents;

each R^(h) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR¹, SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents;

each R^(j) is independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(r) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(p) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alky)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with 1, 2 or 3substituents selected from halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocycloalkyl;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3;

the subscript p is an integer of 1, 2, 3 or 4;

each subscript q is independently an integer of 1, 2, 3 or 4; and

the subscript s is an integer of 1, 2, 3 or 4.

In some embodiments, any two R^(i) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group optionally substituted with 1, 2,or 3 independently selected R^(q) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(q) substituents.

In some embodiments, (1) when L is —C(O)NH—, ring A is not4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a bond,ring A is not 2-benzoxazolyl; (3) when L is —NH—, ring A is not1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; and (4) when L is—C(O)NH—, ring A is not 2-pyridyl.

In some embodiments, (1) when L is —C(O)NH—, ring A is not4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl; (2) when L is a bond,ring A is not 2-benzoxazolyl; (3) when L is —NH—, ring A is not1,7-naphthyridin-8-yl or pyrido[3,2-d]pyrimidin-4-yl; or (4) when L is—C(O)NH—, ring A is not 2-pyridyl.

In some embodiments, provided herein is a compound having Formula (Ia):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyof R¹ or R² is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, —C(O)NH₂, NH₂, —NHC₁₋₄ alkyl and—N(C₁₋₄ alkyl)₂;

R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄alkyl and C₁₋₄ alkoxy are each optionally substituted with 1 or 2substituents independently selected from CN, halo or —C(O)NH₂;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, —COOH,C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl of R⁸ or R⁹ are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

or R⁸ and R⁹ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

or R⁸ and R¹⁰ taken together with the atoms to which they are attachedform 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to oneadditional heteroatoms as ring members selected from O, N or S, whereinthe 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R⁸ and R¹⁰ areeach optionally substituted with 1 or 2 R^(q) substituents;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, —C(O)R^(g), —C(O)OR^(g),—C(O)NR^(g)R^(g), —SO₂R^(g) and —SO₂NR^(g)R^(g), wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁰ or R¹¹ are eachoptionally substituted with 1, 2, or 3 independently selected R^(d)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-memberedheterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is eachoptionally substituted with 1, 2 or 3 R^(f) substituents;

R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂; and

the subscript p is an integer of 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂,—NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxyof R¹ or R² is optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, —C(O)NH₂, NH₂, —NHC₁₋₄ alkyl and—N(C₁₋₄ alkyl)₂; R⁷ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith 1 or 2 substituents independently selected from CN, halo or—C(O)NH₂; R⁸ and R⁹ are each independently selected from H, halo, CN,OH, —COOH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-6 membered heterocycloalkyl, wherein the C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-6 membered heterocycloalkyl of R⁸ or R⁹ areeach optionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

or R⁸ and R⁹ taken together with the carbon atom to which they areattached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or7-membered heterocycloalkyl, each of which is optionally substitutedwith 1 or 2 R^(q) substituents;

or R⁸ and R¹⁰ taken together with the atoms to which they are attachedform 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to oneadditional heteroatoms as ring members selected from O, N or S, whereinthe 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R⁸ and R¹⁰ areeach optionally substituted with 1 or 2 R^(q) substituents; R¹⁰ and R¹¹are each independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, —C(O)R^(g), —C(O)OR^(g),—C(O)NR^(g)R^(g), —SO₂R^(g) and —SO₂NR^(g)R^(g), wherein the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁰ or R¹¹ are eachoptionally substituted with 1, 2, or 3 independently selected R^(d)substituents;

or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they areattached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-memberedheterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is eachoptionally substituted with 1, 2 or 3 R^(f) substituents;

R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂.

In some embodiments, the compound provided herein is a compound havingFormula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the compound provided herein is a compound havingFormula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the compound provided herein is a compound havingFormula (IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the compound provided herein is a compound havingFormula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the compound provided herein is a compound havingFormula (IIIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the compound provided herein is a compound havingFormula (IIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, provided herein are compounds having Formula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5. In one embodiment, ring A ispyridyl, for example, 2-pyridyl. In some embodiments, the subscript n is0, 1 or 2 and each R⁵ is independently C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, NH₂, —NHC₁₋₄ alkyl or—N(C₁₋₄ alkyl)₂. In certain instances, R⁵ is halo or C₁₋₄ alkyl. In someembodiments, the subscript m is 0. In some embodiments, the subscript ris 1 or 2. In some embodiments, R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, —COOH, NH₂, —NHC₁₋₄ alkyl or—N(C₁₋₄ alkyl)₂. In one embodiment, R² is H. In some embodiments, thesubscript p is 1 and R⁸ and R⁹ are each H. In one embodiment, R¹⁰ is H.In some embodiments, R⁸ and R¹⁰ taken together form 4- to 6-memberedheterocycloalkyl, optionally substituted with 1 or 2 R^(q) substituents.In some embodiments, R¹⁰ and R¹¹ taken together form 4- to 6-memberedheterocycloalkyl, optionally substituted with 1 or 2 R^(q) substituents.

In some embodiments, provided herein are compounds having Formula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the variables of Formula (V) are asdefined in any embodiment disclosed herein. In some embodiments, thesubscript r is 1 or 2.

In some embodiments, provided herein are compounds having Formula (VI):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the variables of Formula (VI) are asdefined in any embodiment disclosed herein. In some embodiments, thesubscript r is 1 or 2.

In some embodiments, provided herein are compounds having Formula (VIIa)or (VIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the variables of Formula (VIIa) or(VIIb) are as defined in any embodiment disclosed herein. In someembodiments, the subscript r is 1 or 2.

In some embodiments, provided herein are compounds having Formula(VIIIa) or (VIIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript r is 1, 2, 3, 4 or 5, the other variables of Formula(VIIIa) or (VIIIb) are as defined in any embodiment disclosed herein.

In some embodiments, ring A is 5- to 10-membered heteroaryl or 4- to11-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryland 4- to 11-membered heterocycloalkyl each has 1-4 heteroatoms as ringmembers selected from N, O and S, wherein the N or S atom as ringmembers is optionally oxidized and one or more carbon atoms as ringmembers are each optionally replaced by a carbonyl group; and whereinring A is optionally substituted with 1, 2, 3, 4 or 5 R⁶ substituents.In some embodiments, ring A is optionally substituted with 1, 2 or 3 R⁶substituents. In some embodiments, ring A is optionally substituted with1 or 2 R⁶ substituents.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R¹⁶ is C₁₋₆alkyl; and the wavy line indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; R¹⁶ is C₁₋₆alkyl; and the wavy line indicates the point of attachment to L.

In some embodiments, ring A is selected from:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, ring A is:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L. In some embodiments, ring Ais 2-pyridyl, optionally substituted with 1, 2, 3 or 4 independentlyselected R⁶ substituents.

In some embodiments, ring A is:

wherein each subscript r is an integer of 1, 2, 3, 4 or 5; and the wavyline indicates the point of attachment to L.

In some embodiments, L is a bond, —C(O)NR¹³—, —NR¹³C(O)—, —NR¹³—, or—CH═CH—. In some embodiments, L is a bond or —C(O)NR¹³—. In someembodiments, L is a bond, —NH—, —CH═CH— or —C(O)NH—, wherein thecarbonyl group in the —C(O)NH— linkage is attached to ring A. In someembodiments, L is a bond or —C(O)NH—, wherein the carbonyl group in the—C(O)NH— linkage is attached to ring A.

In some embodiments, L is a bond, —NR¹³—, —(CR¹⁴R¹⁵)^(q)O—,—O(CR¹⁴R¹⁵)_(q)—, —(CR¹⁴R¹⁵)^(q)NR¹³— or —NR¹³—(CR¹⁴R¹⁵)_(q)—, whereinthe subscript q is 1, 2 or 3. In certain instances, R¹⁴ and R¹⁵ are eachindependently H or C₁₋₄ alkyl. In other instances, R¹⁴ and R¹⁵ takentogether form C₃₋₆ cycloalkyl or 4-6-membered heterocycloalkyl, each ofwhich is optionally substituted with 1 or 2 R^(q) substituents.

In some embodiments, L is a bond.

In some embodiment, L is —NR¹³—. In certain instances, R¹³ is H or C₁₋₄alkyl.

In some embodiment, L is —CH₂O— or —OCH₂—.

In some embodiment, L is —NR¹³CH₂— or —CH₂NR¹³. In certain instances,R¹³ is H or C₁₋₄ alkyl.

In some embodiments, the subscript m is 0 or 1. In some embodiments, thesubscript m is 0.

In some embodiments, the subscript n is 0 or 1. In some embodiments, nis 1 and R⁵ is halo or C₁₋₄ alkyl.

In some embodiments, R³ is methyl, halo or CN. In some embodiments, R³is methyl, CN or Cl.

In some embodiments, R¹² is H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, halo, OH,NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂. In some embodiments, R¹² is H orC₁₋₄ alkyl. In some embodiments, R¹² is H.

In some embodiments, R⁷ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, CN,halo, OH, NH₂, —NHC₁₋₄ alkyl or —N(C₁₋₄ alkyl)₂, wherein the C₁₋₄ alkyland C₁₋₄ alkoxy are each optionally substituted with 1 or 2 substituentsindependently selected from CN or halo. In some embodiments, R⁷ is halo,CN, C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyland C₁₋₄ alkoxy of R⁷ are each optionally substituted with CN.

In some embodiments, one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and theother is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH, wherein the C₁₋₄alkyl and C₁₋₄ alkoxy of R¹ or R² is optionally substituted with 1 or 2substituents independently selected from C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, CN, halo, OH, and —NH₂. In some embodiments, one of R¹and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H or C₁₋₄ alkyl. In someembodiments, one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other isH.

In some embodiments, R² is H, halo, C₁₋₄ alkyl or C₁₋₄ alkoxy.

In some embodiments, R¹ is H, halo, C₁₋₄ alkyl or C₁₋₄ alkoxy.

In some embodiments, the subscript p is 1, 2, or 3. In some embodiments,the subscript p is 1 or 2. In some embodiments, the subscript p is 1.

In some embodiments, R⁸ and R⁹ are each independently selected from H,halo, CN, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, and C₁₋₄haloalkoxy of R⁸ or R⁹ are eachoptionally substituted with 1, 2 or 3 independently selected R^(q)substituents. In some embodiments, R⁸ and R⁹ are each independentlyselected from H, halo, C₁₋₄ alkyl, and C₁₋₄ alkoxy. In some embodiments,R⁸ and R⁹ are each independently selected from H and C₁₋₄ alkyl.

In some embodiments, R⁸ and R⁹ are each H.

In some embodiments, R¹⁰ is H.

In some embodiments, R¹¹ is 2-hydroxyethyl,[1-(hydroxymethyl)cyclopropyl]methyl or[1-(hydroxymethyl)cyclobutyl]methyl.

In some embodiments, —NR¹⁰R¹¹ is (2-hydroxyethyl)amino,2-carboxy-1-piperidinyl, 2-oxooxazolidin-3-yl,[1-(hydroxymethyl)cyclopropyl]methylamino or[1-(hydroxymethyl)cyclobutyl]methylamino.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents; L is a bond,—C(O)NR¹³—, or —NR¹³C(O)—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H or C₁₋₄alkyl, wherein the C₁₋₄ alkyl of R¹ or R² is optionally substituted with1 or 2 substituents independently selected from C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, halo, OH, —COOH, —C(O)NH₂, NH₂, —NHC₁₋₄alkyl and —N(C₁₋₄ alkyl)₂;

R³ is methyl, halo, or CN;

R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, or OH;

R⁵ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, or OH;

each R⁶ is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, NO₂, OR^(a),SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), and NR^(a)C(O)R^(a), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R⁶ are each optionallysubstituted with 1 or 2 R^(b) substituents;

R⁷ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, OH, or —COOH, wherein the C₁₋₄alkyl and C₁₋₄ alkoxy are each optionally substituted with 1 or 2substituents independently selected from CN, halo or —C(O)NH₂;

R⁸ and R⁹ are each independently selected from H, halo, CN, OH, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy, wherein theC₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R⁸ or R⁹are each optionally substituted with 1 or 2 independently selected R^(q)substituents;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆ haloalkyl of R¹⁰ or R¹¹ areeach optionally substituted with 1 or 2 independently selected R^(f)substituents;

R¹² is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,halo, and OH;

each R¹³ is independently H, C₁₋₆ haloalkyl or C₁₋₆ alkyl optionallysubstituted with a substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, halo, and OH;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and halo;

each R^(e) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c);

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R^(o) are each optionally substituted with 1 or 2R^(f) substituents independently selected from C₁₋₄ alkyl,C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), and NR^(g)C(O)R^(g);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(q) is independently selected from halo, OH, CN, —COOH, NH₂,—NH—C₁₋₆ alkyl, —N(C₁₋₆ alky)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,and C₁₋₆ haloalkoxy;

the subscript m is an integer of 0, 1, 2 or 3;

the subscript n is an integer of 0, 1, 2 or 3; and

the subscript p is an integer of 1, 2, 3 or 4.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents;

L is a bond, —C(O)NR¹³—, or —NR¹³C(O)—;

one of R¹ and R² is —(CR⁸R⁹)_(p)—NR¹⁰R¹¹ and the other is H;

R³ is methyl;

R⁴ is C₁₋₄ alkyl, halo, or OH;

R⁵ is C₁₋₄ alkyl or halo;

each R⁶ is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R⁶ are each optionally substitutedwith 1 R^(b) substituent;

R⁷ is CN or halo;

R⁸ and R⁹ are each independently selected from H or C₁₋₄ alkyl;

R¹⁰ and R¹¹ are each independently selected from H or C₁₋₆ alkyloptionally substituted with 1 R^(f) substituent;

R¹² is H;

each R¹³ is independently H or C₁₋₆ alkyl optionally substituted with asubstituent selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, and OH;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, OH, NH₂, OR^(c), C(O)R^(c),C(O)NR^(c)R^(c), C(O)OR^(c), NHR^(c), NR^(c)R^(c), and NR^(o)C(O)R^(c);

each R^(g) is independently selected from H and C₁₋₆ alkyl optionallysubstituted with 1 R^(f) substituent selected from C₁₋₄ alkyl,C₁₋₄haloalkyl, halo, NHOR^(g), OR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), NHR^(g), NR^(g)R^(g), and NR^(g)C(O)R^(g);

each R^(g) is independently selected from H and C₁₋₆ alkyl;

the subscript m is an integer of 0 or 1;

the subscript n is an integer of 0 or 1; and

the subscript p is an integer of 1, 2 or 3.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “Cn-m alkenyl” refers to an alkenylgroup having n to m carbons. In some embodiments, the alkenyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groupsinclude, but are not limited to, ethenyl, n-propenyl, isopropenyl,n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.

Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized □ (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In someembodiments, aryl groups have from 6 to about 10 carbon atoms. In someembodiments aryl groups have 6 carbon atoms. In some embodiments arylgroups have 10 carbon atoms. In some embodiments, the aryl group isphenyl. In some embodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-14, or 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14ring-forming carbons (C₃₋₁₄). In some embodiments, the cycloalkyl grouphas 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ringmembers, or 3 to 4 ring members. In some embodiments, the cycloalkylgroup is monocyclic. In some embodiments, the cycloalkyl group ismonocyclic or bicyclic. In some embodiments, the cycloalkyl group is aC₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atoms of acycloalkyl group can be optionally oxidized to form an oxo or sulfidogroup. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-14ring members, 4-10 ring members, 4-7 ring members, or 4-6 ring members.Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6-and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups caninclude mono- or bicyclic or polycyclic (e.g., having two or three fusedor bridged rings) ring systems or spirorcycles. In some embodiments, theheterocycloalkyl group is a monocyclic group having 1, 2 or 3heteroatoms independently selected from nitrogen, sulfur and oxygen.Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl groupcan be optionally oxidized to form an oxo or sulfido group or otheroxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.) or anitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, and thiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

One or more constituent atoms of the compounds of the invention can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound of the present disclosure can be replaced or substituted bydeuterium. In some embodiments, the compound includes two or moredeuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods forincluding isotopes into organic compounds are known in the art.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., JPharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I) can be prepared, e.g., using a process asillustrated in Schemes 1-3.

The compounds of Formula I can be prepared according to Scheme 1. Thehalo group (e.g., Hal¹=Cl, Br, I) of biphenyl compounds 1-1 can beconverted to the boronic esters 1-2 under standard borylation conditions[e.g., in the presence of bis(pinacolato)diboron and a palladiumcatalyst, such as, Pd(dppf)Cl₂]. Boronic esters 1-2 can react with theheteroaryl halides 1-3 (e.g., Hal²=Cl, Br, I) under standard Suzukicoupling conditions (e.g., in the presence of a palladium catalyst and asuitable base) to give the N-bridged bicyclic compounds I.

Alternatively, the compounds of Formula I can be prepared according toScheme 2. Boronic esters 2-1 can react with the heteroaryl halides 2-2(e.g., Hal²=Cl, Br, I) under standard Suzuki coupling condition (e.g.,in the presence of a palladium catalyst and a suitable base) to give theN-bridged bicyclic compounds 2-3, which can react with boronic ester 2-4to give the compounds of Formula I.

The triazole-containing heteroaryl halides of formula 3-4 (Hal² is ahalide such as Br or I) can be formed according to Scheme 3. Coupling ofamino heterocycles 3-1 with ethoxycarbonyl isothiocyanate 3-2, followedby treatment with hydroxylamine hydrochloride and diisopropylethylamine(DIPEA) can form N-bridged heteroaryl amines 3-3. Conversion of theprimary amines 3-3 to halides can be achieved under Sandmeyer reactionconditions [i.e. in the presence of tert-butyl nitrite and a halogensources such as CuBr₂ or I₂] to generate the N-bridged heteroarylhalides 3-4.

III. Uses of the Compounds

Compounds of the present disclosure can inhibit the activity ofPD-1/PD-L1 protein/protein interaction and, thus, are useful in treatingdiseases and disorders associated with activity of PD-1 and the diseasesand disorders associated with PD-L1 including its interaction with otherproteins such as PD-1 and B7-1 (CD80). In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance immunity in cancer, chronic infection orsepsis, including enhancement of response to vaccination. In someembodiments, the present disclosure provides a method for inhibiting thePD-1/PD-L1 protein/protein interaction. The method includesadministering to an individual or a patient a compound of Formula (I) orof any of the formulas as described herein, or of a compound as recitedin any of the claims and described herein, or a pharmaceuticallyacceptable salt or a stereoisomer thereof. The compounds of the presentdisclosure can be used alone, in combination with other agents ortherapies or as an adjuvant or neoadjuvant for the treatment of diseasesor disorders, including cancer or infection diseases. For the usesdescribed herein, any of the compounds of the disclosure, including anyof the embodiments thereof, may be used.

The compounds of the present disclosure inhibit the PD-1/PD-L1protein/protein interaction, resulting in a PD-1 pathway blockade. Theblockade of PD-1 can enhance the immune response to cancerous cells andinfectious diseases in mammals, including humans. In some embodiments,the present disclosure provides treatment of an individual or a patientin vivo using a compound of Formula (I) or a salt or stereoisomerthereof such that growth of cancerous tumors is inhibited. A compound ofFormula (I) or of any of the formulas as described herein, or a compoundas recited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used to inhibit the growth of canceroustumors. Alternatively, a compound of Formula (I) or of any of theformulas as described herein, or a compound as recited in any of theclaims and described herein, or a salt or stereoisomer thereof, can beused in conjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient. The method includes administering to the individual orpatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-Ll.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer, lungcancer (e.g. non-small cell lung cancer and small cell lung cancer),squamous cell head and neck cancer, urothelial cancer (e.g., bladder)and cancers with high microsatellite instability (MSI^(high)).Additionally, the disclosure includes refractory or recurrentmalignancies whose growth may be inhibited using the compounds of thedisclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

PD-1 pathway blockade with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus andarboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp.,Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosomabrucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, andNippostrongylus brasiliensis.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors or one ore moretherapies for the treatment of diseases, such as cancer or infections.Examples of diseases and indications treatable with combinationtherapies include those as described herein. Examples of cancers includesolid tumors and liquid tumors, such as blood cancers. Examples ofinfections include viral infections, bacterial infections, fungusinfections or parasite infections. For example, the compounds of thepresent disclosure can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR,PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K(alpha, beta, gamma, delta), CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4,fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC,TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer or infections. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancer and infections include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat, NLG919,and BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), aTDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), aPI3K-gamma inhibitor such as PI3K-gamma selective inhibitor, a Piminhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor,bromo and extra terminal family members inhibitors (for example,bromodomain inhibitors or BET inhibitors such as INCB54329 andINCB57643), a poly ADP ribose polymerase (PARP) inhibitor such asrucaparib, olaparib, niraparib, veliparib, or talazoparib, and anadenosine receptor antagonist or combinations thereof.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK,PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MED14736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MED14736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments,the OX40L fusion protein is MEDI6383.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, Toll receptor agonists, STING agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate,panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium,pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib, streptozocin,sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide,testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene,tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin,vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib,talazoparib and zoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB (e.g. urelumab, utomilumab), antibodiesto PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.).Examples of antibodies to PD-1 and/or PD-L1 that can be combined withcompounds of the present disclosure for the treatment of cancer orinfections such as viral, bacteria, fungus and parasite infectionsinclude, but are not limited to, nivolumab, pembrolizumab, MPDL3280A,MEDI-4736 and SHR-1210.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™)

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 □g/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician.

The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to labeledcompounds of the invention (radio-labeled, fluorescent-labeled, etc.)that would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1protein in tissue samples, including human, and for identifying PD-L1ligands by inhibition binding of a labeled compound. Accordingly, thepresent invention includes PD-1/PD-L1 binding assays that contain suchlabeled compounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). It is to be understood that a “radio-labeled”compound is a compound that has incorporated at least one isotope thatis radioactive (e.g., radionuclide). Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N,¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro PD-L1 protein labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful. In some embodiments the radionuclide isselected from the group consisting of ³H, ¹⁴C, ¹²⁵, ³⁵S and ⁸²Br.Synthetic methods for incorporating radio-isotopes into organiccompounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a PD-L1 protein bymonitoring its concentration variation when contacting with the PD-L1protein, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a PD-L1 protein (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the PD-L1 protein directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of PD-L1 including its interaction with other proteins suchas PD-1 and B7-1 (CD80), such as cancer or infections, which include oneor more containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of PD-1/PD-L1 protein/protein interaction according to atleast one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Example 1N-(3′-(8-chloro-6-((2-hydroxyethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide

Step 1: ethyl({[3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino}carbonothioyl)carbamate

To a solution of (6-amino-5-chloropyridin-3-yl)methanol (649 mg, 4.09mmol) in 1,4-dioxane (26.5 mL, 340 mmol) was added ethoxycarbonylisothiocyanate (0.694 mL, 6.14 mmol). The reaction mixture was stirredat 50° C. for 2 h. The crude was concentrated. The residue was directlyused for the next step. LC-MS calculated for C₁₀H₁₃ClN₃O₃S (M+H)⁺:m/z=290.0; found: 290.0.

Step 2: (2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

Hydroxylamine hydrochloride (0.566 g, 8.14 mmol) was added to a solutionof ethyl({[3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino}carbonothioyl)carbamate(1.18 g, 4.07 mmol) in methanol (15 mL, 370 mmol)/ethanol (15 mL, 260mmol), followed by N,N-diisopropylethylamine (1.42 mL, 8.14 mmol). Thereaction mixture was then stirred at 50° C. for 3 h. The crude wascooled. The precipitate was filtered to give the desired product 728 mg(90% yield, two steps). LC-MS calculated for C₇H₈ClN₄O (M+H)⁺:m/z=199.0; found: 199.0.

Step 3: (2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

tert-Butyl nitrite (0.728 mL, 6.12 mmol) was added to a suspension of(2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (0.811 g,4.08 mmol) and copper(II) bromide (1.37 g, 6.12 mmol) in acetonitrile(19.1 mL, 365 mmol). The mixture was stirred at room temperature for 1h. The reaction mixture was diluted with DCM and washed with water. Theorganic phase was dried over a drying agent, filtered and concentratedto almost dryness. The residue was filtered to give the pure product.The filtrate also contained some product and was purified bychromatography on silica gel to give the desired product (combined, 1.06g, 99% yield). LC-MS calculated for C₇H₆BrClN₃O (M+H)⁺: m/z=261.9 and263.9; found: 261.9 and 263.9.

Step 4:(2-(3-bromo-2-methylphenyl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

A mixture of2-(3-bromo-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (727mg, 2.448 mmol),(2-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (612 mg,2.332 mmol), Pd(PPh₃)₄ (539 mg, 0.466 mmol) and potassium phosphate,tribasic (990 mg, 4.66 mmol) in dioxane (11.1 mL)/water (555 μL) wasstirred at 90° C. for 1 h. The crude was diluted with DCM, dried over adrying agent, filtered and concentrated. The residue was purified bychromatography on silica gel to give the desired product 516 mg (63%yield). LC-MS calculated for C₁₄H₁₂BrClN₃O (M+H)⁺: m/z=352.0 and 354.0;found: 352.1 and 354.1.

Step 5:(2-(3′-amino-2,2′-dimethylbiphenyl-3-yl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

A mixture of2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (102 mg,0.438 mmol),(2-(3-bromo-2-methylphenyl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol(147 mg, 0.417 mmol), Pd(PPh₃)₄ (96 mg, 0.083 mmol) and potassiumphosphate, tribasic (177 mg, 0.834 mmol) in dioxane (1985 μL)/water (99μl) was stirred at 90° C. for 1 h. The crude was diluted with DCM,dried, filtered and concentrated. The residue was purified bychromatography on silica gel to give the desired product 141 mg (89%yield). LC-MS calculated for C₂₁H₂₀ClN₄O (M+H)⁺: m/z=379.1; found:379.1.

Step 6:N-(3′-(8-chloro-6-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-(dimethoxymethyl)picolinamide

Potassium tert-butoxide in THF (1 M, 774 μL, 0.774 mmol) was addeddropwise to the solution of(2-(3′-amino-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol(97.8 mg, 0.258 mmol) and methyl 5-(dimethoxymethyl)picolinate (164 mg,0.774 mmol) in THF (1291 μL) at 0° C. The mixture was stirred at roomtemperature for 30 min. The crude was diluted with DCM, dried over adrying agent, filtered and concentrated. The residue was purified bychromatography (2-10% MeOH/DCM) on silica gel to give the desiredproduct 74.5 mg (52% yield). LC-MS calculated for C₃₀H₂₉ClN₅O₄(M+H)⁺:m/z=558.2; found: 558.4.

Step 7:N-(3′-(8-chloro-6-formyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-(dimethoxymethyl)picolinamide

Dess-Martin periodinane (85 mg, 0.200 mmol) was added to the suspensionofN-(3′-(8-chloro-6-(hydroxymethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide(74.5 mg, 0.134 mmol) in DCM (668 μl). The mixture was stirred at roomtemperature for 1 h. The mixture was quenched with aq. sodiumthiosulfate and extracted with DCM. The organic phase was dried over adrying agent, filtered and concentrated. The residue was purified bychromatography (30-60% EtOAc/Hex) on silica gel to give the desiredproduct. LC-MS calculated for C₃₀H₂₇ClN₅O₄ (M+H)⁺: m/z=556.2; found:556.2.

Step 8:N-(3′-(8-chloro-6-formyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-formylpicolinamide

TFA (64.8 μl, 0.842 mmol) was added to the solution ofN-(3′-(8-chloro-6-formyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-(dimethoxymethyl)picolinamide(11.7 mg, 0.021 mmol) in DCM (42.1 μL). The mixture was stirred at roomtemperature for 1 h. The mixture was quenched with aq. sodium carbonateand extracted with DCM. The organic phase was dried over a drying agent,filtered and concentrated. The residue was directly used for the nextstep. LC-MS calculated for C₂₈H₂₁ClN₅O₃(M+H)⁺: m/z=510.1; found: 510.2.

Step 9:N-(3′-(8-chloro-6-((2-hydroxyethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethylbiphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide

A mixture ofN-(3′-(8-chloro-6-formyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-5-formylpicolinamide(9.9 mg, 0.019 mmol), 2-aminoethan-1-ol (5.93 mg, 0.097 mmol) in DMF(194 μl) was stirred at room temperature for 1 h. The mixture was cooledto −78° C. NaBH4 (1.469 mg, 0.039 mmol) was added. The reaction wasstirred at room temperature for 1 h. The crude was diluted with MeOH andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₃₂H₃₅ClN₇O₃(M+H)⁺:m/z=600.2; found 600.2.

Example 2N-(2-chloro-3′-(8-chloro-6-((2-hydroxyethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2′-methylbiphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide

The title compound was prepared using similar procedures as describedfor Example 1. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₁H₃₂Cl₂N₇O₃ (M+H)⁺: m/z=620.2; found 620.2.

Example 3N-(2-chloro-3′-(8-cyano-6-((2-hydroxyethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2′-methylbiphenyl-3-yl)-5-((2-hydroxyethylamino)methyl)picolinamide

A mixture ofN-(2-chloro-3′-(8-chloro-6-(((2-hydroxyethyl)amino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide(4.0 mg, 6.45 μmol), potassium ferrocyanide(II) trihydrate (1.089 mg,2.58 μmol), KOAc (0.127 mg, 1.289 μmol) and tBuXPhos Pd G3 (0.512 mg,0.645 μmol) was stirred at 90° C. for 30 min. The crude was diluted withMeOH and filtered. The filtrate was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₂H₃₂ClN₈O₃(M+H)⁺: m/z=611.2; found 611.2.

Example 42-((8-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methylamino)ethanol

Step 1:2-((2-(3-bromo-2-methylphenyl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methylamino)ethanol

The title compound was prepared using similar procedures as describedfor Example 1, Step 7 and 8, from(2-(3-bromo-2-methylphenyl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol(Example 1, Step 4). LC-MS calculated for C₁₆H₁₇BrClN₄O (M+H)⁺:m/z=395.0 and 397.0; found 395.0 and 397.0.

Step 2: tert-butyl2-(3′-(8-chloro-6-((2-hydroxyethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethylbiphenyl-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(9.5 mg, 0.021 mmol),2-(((2-(3-bromo-2-methylphenyl)-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)amino)ethan-1-ol(9.06 mg, 0.023 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos-Pd-G2, Aldrich, cat #741825, 3.3 mg, 4.2 μmol) and potassiumphosphate, tribasic (8.84 mg, 0.042 mmol) in dioxane (99 μL)/water (4.96μL) was stirred at 90° C. for 1 h. The crude was concentrated.

The residue was directly used for the next step. LC-MS calculated forC₃₄H₃₈ClN₆O₃S (M+H)⁺: m/z=645.2; found 645.2.

Step 3:2-((8-chloro-2-(2,2′-dimethyl-3′-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methylamino)ethanol

HCl in dioxane (136 μl, 0.542 mmol) was added to the solution oftert-butyl2-(3′-(8-chloro-6-(((2-hydroxyethyl)amino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(7.0 mg, 10.85 μmol) in MeOH (54.2 μl). The mixture was stirred at roomtemperature for 20 min. The crude was diluted with MeOH and filtered.The filtrate was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₂₉H₃₀ClN₆OS (M+H)⁺: m/z=545.2; found 545.2.

Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)Binding Assay

The assays were conducted in a standard black 384-well polystyrene platewith a final volume of 20 μL. Inhibitors were first serially diluted inDMSO and then added to the plate wells before the addition of otherreaction components. The final concentration of DMSO in the assay was1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4)with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein(19-238) with a His-tag at the C-terminus was purchased fromAcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) withFc tag at the C-terminus was also purchased from AcroBiosystems(PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay bufferand 10 μL was added to the plate well. Plates were centrifuged andproteins were preincubated with inhibitors for 40 minutes. Theincubation was followed by the addition of 10 μL of HTRF detectionbuffer supplemented with Europium cryptate-labeled anti-human IgG(PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated toSureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). Aftercentrifugation, the plate was incubated at 25° C. for 60 min. beforereading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Finalconcentrations in the assay were −3 nM PD1, 10 nM PD-L1, 1 nM europiumanti-human IgG and 20 nM anti-His-Allophycocyanin. IC₅₀ determinationwas performed by fitting the curve of percent control activity versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Compounds of the present disclosure, as exemplified in Examples 1-4,showed IC₅₀ values in the following ranges: +=IC₅₀≤10 nM; ++=10nM<IC₅₀≤100 nM; +++=100 nM<IC₅₀≤1000 nM

Data obtained for the Example compounds using the PD-1/PD-L1 homogenoustime-resolved fluorescence (HTRF) binding assay described in Example Ais provided in Table 1.

TABLE 1 PD-1/PD-L1 HTRF Example IC₅₀ (nM) 1 + 2 + 3 + 4 +

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1-31. (canceled)
 32. A method of inhibiting PD-1/PD-L1 interaction, saidmethod comprising administering to a patient a compound of Formula(IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents; L is a bond,—C(O)NR¹³—, or —NR¹³C(O); R³ is methyl, halo, or CN; R⁵ is C₁₋₄ alkyl,C₁₋₄ alkoxy, CN, halo, or OH; each R⁶ is independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a),NR^(a)R^(a), and NR^(a)C(O)R^(a), wherein the C₁₋₆ alkyl, C₂ alkenyl,and C₂₋₆ alkynyl of R⁶ are each optionally substituted with 1 or 2 R^(b)substituents; R⁷ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, OH, or —COOH,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith 1 or 2 substituents independently selected from CN, halo or—C(O)NH₂; R⁸ and R⁹ are each independently selected from H, halo, CN,OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy,wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxyof R⁸ or R⁹ are each optionally substituted with 1 or 2 independentlyselected R^(q) substituents; R¹⁰ and R¹¹ are each independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆haloalkyl of R¹⁰ or R¹¹ are each optionally substituted with 1 or 2independently selected R^(f) substituents; each R¹³ is independently H,C₁₋₆ haloalkyl or C₁₋₆ alkyl optionally substituted with a substituentselected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CN, halo, and OH; each R^(a) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(b)substituent is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c), SR^(c),C(O)R^(c), C(O)NR^(c)R^(c)C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c); each R^(c) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(c)are each optionally substituted with 1 or 2 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g),NR^(g)R^(g), and NR^(g)C(O)R^(g); each R^(g) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; eachR^(q) is independently selected from halo, OH, CN, —COOH, NH₂, —NH—C₁₋₆alkyl, —N(C₁₋₆ alky)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆haloalkoxy; and the subscript p is an integer of 1, 2, 3 or
 4. 33. Amethod of treating a disease or disorder associated with inhibition ofPD-1/PD-L1 interaction, said method comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents; L is a bond,—C(O)NR¹³—, or —NR¹³C(O)—; R³ is methyl, halo, or CN; R⁵ is C₁₋₄ alkyl,C₁₋₄ alkoxy, CN, halo, or OH; each R⁶ is independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ haloalkyl, C₁₋₆haloalkoxy, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a),NR^(a)R^(a), and NR^(a)C(O)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R⁶ are each optionally substituted with 1 or 2 R^(b)substituents; R⁷ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, OH, or —COOH,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith 1 or 2 substituents independently selected from CN, halo or—C(O)NH₂; R⁸ and R⁹ are each independently selected from H, halo, CN,OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy,wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxyof R⁸ or R⁹ are each optionally substituted with 1 or 2 independentlyselected R^(q) substituents; R¹⁰ and R¹¹ are each independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆haloalkyl of R¹⁰ or R¹¹ are each optionally substituted with 1 or 2independently selected R^(f) substituents; each R¹³ is independently H,C₁₋₆ haloalkyl or C₁₋₆ alkyl optionally substituted with a substituentselected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CN, halo, and OH; each R^(a) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(b)substituent is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c), SR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c); each R^(c) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(c)are each optionally substituted with 1 or 2 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g),NR^(g)R^(g), and NR^(g)C(O)R^(g); each R^(g) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; eachR^(q) is independently selected from halo, OH, CN, —COH, NH₂, —NH—C₁₋₆alkyl, —N(C₁₋₆ alky), C₁₋₆ alkyl C₁₋₆alkoxy, C₁₋₆ haloalkyl, and C₁₋₆haloalkoxy; and the subscript p is an integer of 1, 2, 3 or
 4. 34. Amethod of enhancing, stimulating and/or increasing the immune responsein a patient, said method comprising administering to the patient inneed thereof a therapeutically effective amount of a compound of Formula(IIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: ring A is 5- to 10-membered heteroaryl or 4- to 11-memberedheterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 4- to11-membered heterocycloalkyl each has 1-4 heteroatoms as ring membersselected from N, O and S, wherein the N or S atom as ring members isoptionally oxidized and one or more carbon atoms as ring members areeach optionally replaced by a carbonyl group; and wherein ring A isoptionally substituted with 1 or 2 R⁶ substituents; L is a bond,—C(O)NR¹³—, or —NR¹³C(O; R³ is methyl, halo, or CN; R⁵ is C₁₋₄ alkyl,C₁₋₄ alkoxy, CN, halo, or OH; each R⁶ is independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a)OC(O)NR^(a)R^(a), NR^(a),NR^(a)R^(a), and NR^(a)C(O)R^(a), wherein the C₆ alkyl, C₂ alkenyl, andC₂₋₆ alkynyl of R⁶ are each optionally substituted with 1 or 2 R^(b)substituents; R⁷ is C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, halo, OH, or —COOH,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith 1 or 2 substituents independently selected from CN, halo or—C(O)NH₂; R⁸ and R⁹ are each independently selected from H, halo, CN,OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy,wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxyof R⁸ or R⁹ are each optionally substituted with 1 or 2 independentlyselected R^(q) substituents; R¹⁰ and R¹¹ are each independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl and C₁₋₆haloalkyl of R¹⁰ or R¹¹ are each optionally substituted with 1 or 2independently selected R^(f) substituents; each R¹³ is independently H,C₁₋₆ haloalkyl or C₁₋₆ alkyl optionally substituted with a substituentselected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CN, halo, and OH; each R^(a) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(b)substituent is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c), SR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c),NHR^(c), NR^(c)R^(c), and NR^(c)C(O)R^(c); each R^(c) is independentlyselected from H, C₁₋₆ alkyl C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(c)are each optionally substituted with 1 or 2 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g),NR^(g)R^(g), and NR^(g)C(O)R^(g); each R^(g) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; eachR^(q) is independently selected from halo, OH, CN, —COOH, NH₂, —NH—C₁₋₆alkyl, —N(C₁₋₆ alky), C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆haloalkoxy; and the subscript p is an integer of 1, 2, 3 or 4.